According to the United Nations Children's Fund (UNICEF) and the World Health Organization (WHO), diarrhea disease is the second leading cause of death and a main cause of malnutrition in children under five years old. A significant proportion of diarrhea disease can be prevented through safe drinking-water and adequate sanitation and hygiene.
Diarrhea is characterized by an increase in the frequency of bowel movements compared to normal bowel movement or a decrease in the formation of a stool. Although changes in frequency of bowel movements and looseness of stools can vary independently of each other, changes often occur in both.
In most cases, diarrhea signs and symptoms usually last a couple of days. But sometimes diarrhea can last for weeks. In these situations, diarrhea can be a sign of a serious disorder, such as inflammatory bowel disease, or a less serious condition, such as irritable bowel syndrome.
Diarrhea can be an infectious bacterial or viral disorder caused by parasites. The diarrhea may also be a non-infectious diarrhea caused by food poisoning, food additives, food allergies, malabsorption syndromes (like gluten or lactose intolerance), antibiotic therapies, diseases of the intestines (Crohn's disease, ulcerative colitis), etc. Typical treatment is to give fluids to prevent dehydration and continued feeding while administering drugs for the underlying cause.
In cases of infectious disorder caused by bacteria, the pathogenic mechanisms of Escherichia coli (a gram-negative bacteria), that induced diarrhea, probably involves secretion of a heat stable toxin (STa).
Thus, the present inventor's efforts to develop new pyridopyrimidine derivative compounds inhibitors of cyclic nucleotide synthesis caused by stable toxin of Escherichia coli (STa). The STa induces diarrhea when it binds to intestinal epithelial cell membrane receptor, guanylyl cyclase type C (GC-C). This activates the enzyme to convert guanosine triphosphate (GTP) to cyclic guanosine 3′,5′-monophosphate (cGMP), causing intracellular levels of cGMP to spike. This in turn induces activation of a cGMP-dependent protein kinase and chloride-ion channel, cystic fibrosis transmembrane conductance regulator (CFTR). Activation of CFTR triggers the flux of chloride ions into the intestinal lumen and the accumulation of water and sodium ions, thus causing diarrhea.
International Publication No. WO 2008/008704 describes inhibitors of cyclic nucleotide synthesis and their use for therapy of various diseases.
Another class of inhibitor of the cAMP and cGMP synthesis and inhibitor of cyclic nucleotide synthesis is described in the publication by TANIFUM [E. A. TANIFUM et al., “Novel pyridopyrimidine derivatives as inhibitors of stable toxin a (STa) induced cGMP synthesis”. Bioorganic & Medicinal Chemistry Letters, 2009, 19:3067-3071]. According to this publication, one of the best compounds identified was Compound 24 (FPIPP), with the following structural form:

Also according to TANIFUM [E. A. TANIFUM et al., “Novel pyridopyrimidine derivatives as inhibitors of stable toxin a (STa) induced cGMP synthesis”. Bioorganic & Medicinal Chemistry Letters, 2009, 19:3067-3071], the development of drugs that are effective against the physiological mechanisms that cause the imbalance of fluids in the intestine would be a significant addition in therapeutic arsenal.
Based on the above, the inventor of the present invention developed new compounds, new derivatives of pyridopyrimidine, that can be used in treatment, prevention or amelioration of symptoms of diarrhea.